Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity

doi:10.1016/j.immuni.2024.01.002

. 2024 Feb 13;57(2):319-332.e6.

doi: 10.1016/j.immuni.2024.01.002. Epub 2024 Jan 30.

Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity

Affiliations

¹ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
² Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Immunology, Allergy and Rheumatology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
³ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁴ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁵ The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA; Department of Pediatrics and Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁷ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: theresa.alenghat@cchmc.org.

PMID: 38295798
PMCID: PMC10901458 (available on 2025-02-13)
DOI: 10.1016/j.immuni.2024.01.002

Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity

Emily M Eshleman et al. Immunity. 2024.

. 2024 Feb 13;57(2):319-332.e6.

doi: 10.1016/j.immuni.2024.01.002. Epub 2024 Jan 30.

Authors

Affiliations

¹ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
² Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Immunology, Allergy and Rheumatology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
³ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁴ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁵ The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA; Department of Pediatrics and Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
⁷ Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: theresa.alenghat@cchmc.org.

PMID: 38295798
PMCID: PMC10901458 (available on 2025-02-13)
DOI: 10.1016/j.immuni.2024.01.002

Abstract

Tuft cells in mucosal tissues are key regulators of type 2 immunity. Here, we examined the impact of the microbiota on tuft cell biology in the intestine. Succinate induction of tuft cells and type 2 innate lymphoid cells was elevated with loss of gut microbiota. Colonization with butyrate-producing bacteria or treatment with butyrate suppressed this effect and reduced intestinal histone deacetylase activity. Epithelial-intrinsic deletion of the epigenetic-modifying enzyme histone deacetylase 3 (HDAC3) inhibited tuft cell expansion in vivo and impaired type 2 immune responses during helminth infection. Butyrate restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids blocked tuft cell expansion. Collectively, these data define a HDAC3 mechanism in stem cells for tuft cell differentiation that is dampened by a commensal metabolite, revealing a pathway whereby the microbiota calibrate intestinal type 2 immunity.

Keywords: HDAC3; butyrate; development; epigenetics; intestine; microbiota; organoid; stem cell; tuft cell; type 2 immunity.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Comment in

Host-microbial crosstalk relies on "tuft" love.
De Santis S, Pizarro TT. De Santis S, et al. Immunity. 2024 Feb 13;57(2):195-197. doi: 10.1016/j.immuni.2024.01.016. Immunity. 2024. PMID: 38354697

Cited by

Dietary and metabolic effects on intestinal stem cells in health and disease.
Shay JES, Yilmaz ÖH. Shay JES, et al. Nat Rev Gastroenterol Hepatol. 2025 Jan;22(1):23-38. doi: 10.1038/s41575-024-00980-7. Epub 2024 Oct 2. Nat Rev Gastroenterol Hepatol. 2025. PMID: 39358589 Review.
Tuft cells in the intestine, immunity and beyond.
Feng X, Flüchter P, De Tenorio JC, Schneider C. Feng X, et al. Nat Rev Gastroenterol Hepatol. 2024 Dec;21(12):852-868. doi: 10.1038/s41575-024-00978-1. Epub 2024 Sep 26. Nat Rev Gastroenterol Hepatol. 2024. PMID: 39327439 Review.
Gut microbiome in the first 1000 days and risk for childhood food allergy.
Davis EC, Monaco CL, Insel R, Järvinen KM. Davis EC, et al. Ann Allergy Asthma Immunol. 2024 Sep;133(3):252-261. doi: 10.1016/j.anai.2024.03.010. Epub 2024 Mar 16. Ann Allergy Asthma Immunol. 2024. PMID: 38494114 Review.
A synbiotic of Anaerostipes caccae and lactulose prevents and treats food allergy in mice.
Hesser LA, Puente AA, Arnold J, Ionescu E, Mirmira A, Talasani N, Lopez J, Maccio-Maretto L, Mimee M, Nagler CR. Hesser LA, et al. Cell Host Microbe. 2024 Jul 10;32(7):1163-1176.e6. doi: 10.1016/j.chom.2024.05.019. Epub 2024 Jun 20. Cell Host Microbe. 2024. PMID: 38906158
Commensal microbe regulation of skin cells in disease.
Gan Y, Zhang J, Qi F, Hu Z, Sweren E, Reddy SK, Chen L, Feng X, Grice EA, Garza LA, Wang G. Gan Y, et al. Cell Host Microbe. 2024 Aug 14;32(8):1264-1279. doi: 10.1016/j.chom.2024.07.020. Cell Host Microbe. 2024. PMID: 39146798 Free PMC article. Review.

See all "Cited by" articles

References

1. Hammad H, and Lambrecht BN (2015). Barrier Epithelial Cells and the Control of Type 2 Immunity. Immunity 43, 29–40. 10.1016/j.immuni.2015.07.007. - DOI - PubMed
1. Ali A, Tan HY, and Kaiko GE (2020). Role of the Intestinal Epithelium and Its Interaction With the Microbiota in Food Allergy. Front. Immunol 11, 1–12.10.3389/fimmu.2020.604054. - DOI - PMC - PubMed
1. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, Cesses P, Garnier L, Pouzolles M, Brulin B, et al. (2016). Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230. 10.1038/nature16527. - DOI - PMC - PubMed
1. Von Moltke J, Ji M, Liang H, and Locksley RM (2016). Tuft cell derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225.10.1038/nature16161. - DOI - PMC - PubMed
1. Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, Gallini CA, Redding K, Margolskee RF, Osborne LC, et al. (2016). Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science (80-, ). 351, 1329–1333. 10.1126/science.aaf1648. - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
- Ovid Technologies, Inc.
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases

[1] Hammad H, and Lambrecht BN (2015). Barrier Epithelial Cells and the Control of Type 2 Immunity. Immunity 43, 29–40. 10.1016/j.immuni.2015.07.007. - DOI - PubMed

[2] Hammad H, and Lambrecht BN (2015). Barrier Epithelial Cells and the Control of Type 2 Immunity. Immunity 43, 29–40. 10.1016/j.immuni.2015.07.007. - DOI - PubMed

[3] Ali A, Tan HY, and Kaiko GE (2020). Role of the Intestinal Epithelium and Its Interaction With the Microbiota in Food Allergy. Front. Immunol 11, 1–12.10.3389/fimmu.2020.604054. - DOI - PMC - PubMed

[4] Ali A, Tan HY, and Kaiko GE (2020). Role of the Intestinal Epithelium and Its Interaction With the Microbiota in Food Allergy. Front. Immunol 11, 1–12.10.3389/fimmu.2020.604054. - DOI - PMC - PubMed

[5] Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, Cesses P, Garnier L, Pouzolles M, Brulin B, et al. (2016). Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230. 10.1038/nature16527. - DOI - PMC - PubMed

[6] Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, Cesses P, Garnier L, Pouzolles M, Brulin B, et al. (2016). Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230. 10.1038/nature16527. - DOI - PMC - PubMed

[7] Von Moltke J, Ji M, Liang H, and Locksley RM (2016). Tuft cell derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225.10.1038/nature16161. - DOI - PMC - PubMed

[8] Von Moltke J, Ji M, Liang H, and Locksley RM (2016). Tuft cell derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225.10.1038/nature16161. - DOI - PMC - PubMed

[9] Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, Gallini CA, Redding K, Margolskee RF, Osborne LC, et al. (2016). Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science (80-, ). 351, 1329–1333. 10.1126/science.aaf1648. - DOI - PMC - PubMed

[10] Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, Gallini CA, Redding K, Margolskee RF, Osborne LC, et al. (2016). Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science (80-, ). 351, 1329–1333. 10.1126/science.aaf1648. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity

Affiliations

Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Abstract

Conflict of interest statement

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases